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Baylor s Beaudet Discusses the Potential of Prenatal Chromosomal Microarray Analysis

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Arthur Beaudet
Chairman,
Department of Molecular and
Human Genetics
Baylor College
of Medicine

Name: Arthur Beaudet

Title: Chairman, Department of Molecular and Human Genetics, Baylor College of Medicine

Education: 1967 — MD, Yale University School of Medicine; 1963 — BSc, College of the Holy Cross.


The Department of Molecular and Human Genetics at Baylor College of Medicine in Houston recently launched a service that provides prenatal chromosomal microarray analysis, a first in the less than five-year-old arena of array comparative genomic hybridization-based diagnostics.

While other companies and labs, like Spectral Genomics and Signature Genomic Laboratories, have been created to meet the need for CMA for diagnosing patients with undetermined chromosomal abnormalities, the prenatal service is uncharted territory, a no man's land of ethical questions, and an opportunity for the technology to prove itself in a vital arena.

The interest in the service came to a head with a cautious editorial in the Dec. 8 issue of Nature that stressed there was an "urgency" for US regulatory agencies, like the US Food and Drug Administration, to take a serious look at emerging genetic diagnostics, such as CMA.

To learn more about the new service, and the logistical and ethical questions swirling about it, BioArray News spoke with Arthur Beaudet, the chairman of the Department of Molecular and Human Genetics at Baylor College of Medicine, last week.

What kind of response have you had to the launch in terms of patients?

It's too early to tell. We did a mail out to geneticists in October and had presentations at the American Society of Human Genetics meeting [in Salt Lake City] at the end of October.

We are just beginning to see a trickle of samples at this point for prenatals. Now we are doing maybe 60 or 70 bloods a week, but we are just beginning to see the very first prenatal samples on a fee basis.

I saw you just launched the fifth version of your chip. How is this chip more comprehensive when compared with version 4.0, and is the change reflected in the cost?

[This chip has] better coverage of telomere regions, coverage of a few additional rare disorders, and coverage of centromeric regions. [It has] 860 clones versus 360 in the earlier version.

[With regards to cost], we started out last year to do $1,900 for blood sample analysis and we've reduced that to $1,500 despite the expansion of the array. We are charging now $1,900 for prenatal analysis, which is more complicated and that includes the cost of studying the parents where appropriate.

We routinely collect samples from both parents when we do a prenatal study. Sometimes — maybe 5-10 percent of the time — we have to do comparisons between the parents and the fetus to see if there's any change that's inherited or de novo, which helps in the interpretation.

In the case of [regular screening], since there's no urgency and no rush, we only ask to get samples on the parents if necessary for interpretation purposes, whereas usually with a prenatal everybody wants a rapid answer, so we have samples collected from the parents and hold them and look at them if we need to.

In the case of [regular screening], since there's no urgency and no rush, we only ask to get samples on the parents if necessary for interpretation purposes, whereas usually with a prenatal everybody wants a rapid answer, so we have samples collected from the parents and hold them and look at them if we need to.

I read recently that you have had a clinical trial involving 98 women. What are your plans with regards to publishing the results of the trial?

Hopefully it will be submitted tomorrow. I can't tell you any more about the content. I risk not getting it published in the preferred journals if I talk about it.

Do you validate your results with fluorescent in situ hybridization or any other technology?

All abnormalities are confirmed by FISH or karyotype at no additional cost. Sometimes the abnormality is only detectable by the array, but in those cases it's usually not a disease-causing abnormality and it's usually present in a parent as well. By and large the confirmations are pretty straight forward. FISH is mainly [used for validation]. We actually have on site the ability to do FISH the next day with any of the 860 clones that are on the array. So we are prepared to do FISH in a one-day turnaround.

What is the overall turnaround for the prenatal testing? What kind of resources do you have?

We are trying to shoot for five to seven working days. We have an every other week meeting of the array team that's doing this. I'd say we have about 25 people at that meeting. Some are interested parties that aren't necessarily involved. As far as talking to the patients, for these prenatal samples it's likely to be done out of town. We do have a consent form that has to be signed. It's not a research [Institutional Review Board] consent form but it's more like a consent form for a surgical procedure or something since it's a relatively new and complicated test.

So any obstetrician or genetic counselor anywhere in the county can get a copy of the consent form from us, review with their patient, and have a sample sent to us.

What is your current affiliation with Spectral Genomics? Do you use any of their technology in your work at BMC?

Baylor and our department own stock in Spectral. We have worked closely with them in the past, but we are print all our own arrays at the moment. We use a chemistry patented by Baylor licensed exclusively to Spectral but we pay them a royalty. Other groups do not use that chemistry.

They currently are offering a Constitutional Chip that's very similar to our version 4. They are interested in trying to get that approved by the FDA. So, they've not wanted to go on to a more complex version 5; they wanted to stick to a more basic version and try to get FDA approval for that.

If they got approval would that make you more likely to use version 4?

We feel like we would still have some advantages and we think that version 5 is better than version 4, so we think that we'd be ahead of the people that would buy version 4 from them but they've got these regulatory issues. If they are going to try to get regulatory approval, they can't be updating it every six months, which we can do. I think any FDA approval would be something of a validation of this approach.

I think that this approach will someday be widely used. It will be approved by one or another FDA mechanism. But as the Nature editorial commented on, it's sort of a no man's land at the moment.

What kind of ethical guidelines does your service follow? Have you sensed any movement on the part of US regulatory agencies that they may be interested in regulating this new area?

Well, we've done prenatal diagnosis for decades now, and with prenatal diagnosis throughout the years there have been various innovations introduced.

There are uncertainties in prenatal diagnosis sometimes. It's not so unusual. A common example of uncertainty would be so-called mosaicism, where, in a sample, an occasional cell has an abnormality but most of the cells don't have the abnormality. And does that really reflect any problem in the fetus or not? There are a variety of kinds of uncertainties that have to be reviewed with the parents and the answers are not always black and white.

As an example, when you do conventional prenatal diagnosis, you detect a condition of 47 chromosomes with XYY. Most individuals with XYY are normal males. But there is some evidence that there are some behavioral problems in these people and there've been some reports that there's a mild predisposition towards various kinds of criminal behavior in mild XYY individuals. But most XYY individuals are in society behaving perfectly normally.

So, we've dealt with the issue about how to inform parents of that. What do they want to do? I think most of the time the parents usually say "If there's any doubt about it, we're not going to terminate the pregnancy. We will only terminate the pregnancy if it's absolutely certain the fetus is affected and it's obviously something pretty bad." Other families will say, "If there's any chance this fetus is at risk of being abnormal, we want to terminate the pregnancy." And people may want to make their own personal decisions, based on certain or partial information.

I don't know if it breaks a lot of new ground. There is a lot of concern [about what happens] if we detect variations we can't interpret, but we haven't found that to be the case to any distressing extent.

I am actually in conversation with a group of investigators that are putting together a proposal to the National Institutes of Health to do a multi-institutional study to try to get greater amount of data in the prenatal setting about the accuracy and what difficulties arise or don't arise. There's a lot happening, all of it in the direction of moving this forward into the clinic.

Can you gauge the response among your colleagues that aren't involved in chromosomal microarray analysis?

I gave a talk to the National Society of Genetic Counselors in the beginning of November. These are very informed people who are counseling women about prenatal diagnosis all the time. I would say that there were two kinds of reaction in the audience. Some was fear that this new kind of technology would have problems; that we are going too fast. There certainly are reservations even among highly informed people about this change.

We think we are familiar with it and comfortable with it and others will be comfortable with it when they learn about it. But certainly there are reservations and concerns. I think that as people learn more about it they'll mostly be satisfied with this technology.

But there are two situations. You have to separate the technology from the overall objection to prenatal diagnosis and termination of pregnancy. If a person thinks that prenatal diagnosis for Down syndrome is a good thing and that it's a good medicine and a good choice for people, then this is better medicine, better choice in my opinion.

If people think that prenatal diagnosis and termination of pregnancy for Down syndrome is wrong, they will think this is wrong as well. If it is unacceptable from an ethical, moral abortion vantage point, then people will be opposed to this test just as they are to the whole procedure of prenatal diagnostics.

But it is important to separate the issue of those that are opposed to abortion on any grounds in any circumstances from those that are concerned that the new technology may have some problems that we are not aware of. I think those are very different concerns.

Have you seen any representatives from the FDA at any of these conferences, or had any dialogue with them?

I have talked to a couple of consultants that used to work for the FDA, and I did have one phone conversation maybe a year and a half ago with one person at the FDA. They have a guideline that was posted almost three years ago that was about complex genetic arrays. I know Spectral Genomics has been interacting with them a good bit. They have been submitting things to them and they want to move down that process. We intend to stay put for the foreseeable future as a homebrew operation, which means we are not obligated to communicate with the FDA.

You have a service. Signature Genomics Laboratories has a service. Do you think that that is going to be the model for this technology?

I think that the service is going to become widespread. I think there are some questions about the regulatory issues as to exactly how it will happen. Right now, all of the large cytogenetic companies — Genzyme, Quest Diagnostics, Mayo Labs, et cetera — all of these people are making plans about how best they could get into this activity. They all understand that it's going to replace conventional chromosome analysis. These companies could do what we are doing. They could set this up internally as a homebrew operation.

There are oligo arrays out there that we have gotten good data from and you can make these same diagnoses with commercially available arrays from Affymetrix or Agilent. But none of those companies has expressed any interest of going through the FDA process, which they think will be long and expensive. But I think that all the major cytogenetic players nationally are just figuring out how best to make the transition, not if they are going to make the transition.

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